Caso Clinico

Understanding lactic acidosis in paracetamol (acetaminophen) poisoning

Anoop D Shah,1 David M Wood,1,2 and Paul I Dargan1,2

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Abstract

Paracetamol (acetaminophen) is one of the most commonly taken drugs in overdose in many areas of the world, and the most common cause of acute liver failure in both the UKand USA. Paracetamol poisoning can result in lactic acidosis in two different scenarios. First, early in the course of poisoning and before the onset of hepatotoxicity in patients with massive ingestion; a lactic acidosis is usually associated with coma. Experimental evidence from studies in whole animals, perfused liver slices and cell cultures has shown that the toxic metabolite of paracetamol,N-acetyl-p-benzo-quinone imine, inhibits electron transfer in the mitochondrial respiratory chain and thus inhibits aerobic respiration. This occurs only at very high concentrations of paracetamol, and precedes cellular injury by several hours. The second scenario in which lactic acidosis can occur is later in the course of paracetamol poisoning as a consequence of established liver failure. Inthese patients lactate is elevated primarily because of reduced hepatic clearance, but in shocked patients there may also be a contribution of peripheral anaerobic respiration because of tissue hypoperfusion. In patients admitted to a liver unit with paracetamol hepatotoxicity, the post-resuscitation arterial lactate concentration has been shown to be a strong predictor of mortality, and isincluded in the modified King's College criteria for consideration of liver transplantation. We would therefore recommend that post-resuscitation lactate is measured in all patients with a severe paracetamol overdose resulting in either reduced conscious level or hepatic failure.

Keywords: acetaminophen, lactate, lactic acidosis, overdose, paracetamol, prognosis
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Introduction
Paracetamol(acetaminophen) is the most commonly taken drug in overdose in the UK and is a common cause of overdose morbidity and mortality [1, 2]. Death is most commonly due to hepatotoxicity and it is the most common cause of acute liver failure (ALF) in the UK [3]. Paracetamol poisoning is also common in other developed countries [4]. In the USA it is involved in more than 50 000 Emergency Department visitsand 400 deaths each year [5].
Paracetamol poisoning has complex effects on cellular metabolism, and may cause lactic acidosis in two different scenarios. First, there are numerous reports of severe early lactic acidosis, often with coma, occurring prior to the onset of hepatotoxicity. These occurred in patients with very large paracetamol overdoses (usually more than 40 g, with peak plasmaparacetamol concentrations typically over 800 mg l−1). Many of these patients did not develop liver damage after treatment with N-acetylcysteine [6,7]. The second scenario occurs later in the course of paracetamol poisoning, in patients with established paracetamol-related hepatotoxicity. In this group, an elevated arterial lactate concentration has been shown to be a strong predictor of death [8, 9].A healthy volunteer study using a single supra-therapeutic (4 g) dose of paracetamol was not associated with hepatotoxicity, but caused two peaks of lactate at 6 and 72 h post-ingestion [10]. These changes in metabolite concentrations are likely to be exaggerated in patients with paracetamol poisoning. This review will explore the circumstances and clinical significance of lactic acidosis inpatients with paracetamol poisoning.
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Methods

We searched MEDLINE (PubMed®) from 1970 to February 2010 for articles containing the terms ‘(acidaemia OR acidemia OR acidosis OR hyperlactatemia OR hyperlactataemia OR lactic OR lactate) AND (paracetamol OR acetaminophen)’ in the title, abstract or keywords. This search returned 324 entries. We reviewed the titles and abstracts of these...